rs72554331

Variant names:

• chrX-38369815-G-A
• rs72554331
• NM_000531.6:c.236G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_000531.6(OTC):​c.236G>A​(p.Gly79Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: OTC NM_000531.6 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 7.81

Genes affected

OTC (HGNC:8512): (ornithine transcarbamylase) This nuclear gene encodes a mitochondrial matrix enzyme. The encoded protein is involved in the urea cycle which functions to detoxify ammonia into urea for excretion. Mutations in this enzyme lead to ornithine transcarbamylase deficiency, which causes hyperammonemia. [provided by RefSeq, May 2022]

ENSG00000250349 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant X-38369815-G-A is Pathogenic according to our data. Variant chrX-38369815-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 11006.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTC	NM_000531.6	c.236G>A	p.Gly79Glu	missense_variant	Exon 3 of 10	ENST00000039007.5	NP_000522.3
OTC	NM_001407092.1	c.236G>A	p.Gly79Glu	missense_variant	Exon 5 of 12		NP_001394021.1
OTC	XM_017029556.2	c.236G>A	p.Gly79Glu	missense_variant	Exon 3 of 9		XP_016885045.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTC	ENST00000039007.5	c.236G>A	p.Gly79Glu	missense_variant	Exon 3 of 10	1	NM_000531.6	ENSP00000039007.4
ENSG00000250349	ENST00000465127.1	c.172-296306G>A		intron_variant	Intron 3 of 8	5		ENSP00000417050.1
OTC	ENST00000488812.1	n.328G>A		non_coding_transcript_exon_variant	Exon 3 of 6	5
OTC	ENST00000643344.1	n.236G>A		non_coding_transcript_exon_variant	Exon 3 of 11			ENSP00000496606.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1080274 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 348298

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Ornithine carbamoyltransferase deficiency Pathogenic:2

Jan 31, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: OTC c.236G>A (p.Gly79Glu) results in a non-conservative amino acid change located in the Aspartate/ornithine carbamoyltransferase, carbamoyl-P binding domian (IPR006132) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 182630 control chromosomes (gnomAD). c.236G>A has been reported in the literature in individuals affected with Ornithine Transcarbamylase Deficiency (Tuchman_1992, McCullough_2000). At least one publication reports experimental evidence evaluating an impact on protein function and this variant affected OTC protein function (Tuchman_2002). The following publications have been ascertained in the context of this evaluation (PMID: 36303552, 37146589, 28324312, 10946359, 11793468, 1480464, 16786505). ClinVar contains an entry for this variant (Variation ID: 11006). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Feb 01, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

-

GenMed Metabolism Lab

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.72	D
BayesDel_noAF	Pathogenic	0.79
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.6	H
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-6.3	D
REVEL	Pathogenic	0.98
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.91		Gain of solvent accessibility (P = 0.0171);
MVP		1.0
MPC		1.2
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.98
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs72554331; hg19: chrX-38229068;